A cellular disintegrin and metalloproteinase (ADAM) is a new family of genes with structural homology to the snake venom metalloproteinases and disintegrins. We screened genes which were selectively expressed in the cachexigenic colon 26 adenocarcinoma subline in vivo. It was found that one novel cDNA clone, identified as a cachexigenic tumor selective gene, encodes a cysteinerich protein which shows a sequence similarity to that of both the snake venom metalloproteinases and thrombospondins. We named this cDNA clone A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-1). ADAMTS1 consists of six domains, 1) a proand 2) a metalloproteinase, 3) a disintegrin-like, 4) a thrombospondin (TSP) homologous domain containing TSP type I motif, 5) a spacer region, and 6) COOH-terminal TSP submotifs. Unlike other ADAMs, ADAMTS-1 does not possess a transmembrane domain and is a putative secretory protein. Therefore, ADAMTS-1 is a new type of ADAM family protein with TSP type I motifs. We demonstrated that the TSP homologous domain containing the TSP type I motif of ADAMTS-1 is functional for binding to heparin. ADAMTS-1 mRNA could be induced by stimulating colon 26 cells with an inflammatory cytokine, interleukin-1, in vitro. Moreover, intravenous administration of lipopolysaccharide in mice selectively induced ADAMTS-1 mRNA in kidney and heart. These data suggest that ADAM-TS-1 may be a gene whose expression is associated with various inflammatory processes as well as development of cancer cachexia.

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Lung cancer is the most common cause of cancer deaths in males and females. Although small-cell lung cancer is sensitive to chemotherapy, it gradually becomes resistant due to the emergence of multidrug-resistant cells. P-glycoprotein (P-gp) encoded by the mdr1 gene is one of the key molecules in MDR. It has been shown to bind anti-cancer drugs, to be an ATPase, and to be localized in the plasma membranes of MDR cells (Hamada and Tsuruo, 1988). Expression of the mdr1 gene was found to be elevated in intrinsically drug-resistant cancers as well as in tumors that acquired drug resistance during chemotherapy (Noonan et al., 1990). Recently, even a low level of P-gp expression was reported to be useful as a marker of resistance to combination chemotherapy in ovarian and small-cell lung cancers (Holzmayer et al., 1992). Thus, the selective killing of tumor cells expressing P-gp seems very important for successful cancer therapy. We found previously that 2 monoclonal antibodies, MRK16 and MRK17, that react with the extracellular domain of P-gp, induced lysis of MDR cancer cells in vitro by inducing antibody-dependent monocyte-mediated cytotoxicity (Hamada and Tsuruo, 1986;Nishioka et al., 1992) and caused rapid regression of subcutaneously established MDR human ovarian cancers (Tsuruo et al., 1989).Many reports have shown that it is very important for successful immunotherapy of cancers to attract effector cells, such as monocytemacrophages and lymphocytes, into the site of tumor growth (Rosenberg, 1992). Much attention has been paid to transduction of cytokine genes into tumor cells not only for analysis of cytokinemediated biological effects on tumor growth, but also for clinical use as tumor vaccines. Previous works demonstrated that the transductions of cytokine genes such as IL-2, IL-4, IL-7, TNF-a, IFN-g and GM-CSF into tumor cells induced regression of tumors (Watanabe et al., 1989;Dranoff et al., 1993;Hock et al., 1993). To enhance the accumulation of killer cells, particularly monocytemacrophages, we focused on MCP-1, also known as monocyte chemotactic and activating factor (MCAF), which is a potent chemoattractant and an activator of monocytes (Furutani et al., 1989). In this study, we transfected MDR human small-cell lung cancer (H69/VP) cells with the MCP-1 gene, and examined whether MCP-1 gene transduction enhanced the therapeutic efficacy of anti-P-gp (MRK16) MAb against MDR cancers. We found that MCP-1-producing clones exhibited similar tumorigenicity and in vivo growth rates as control clones. However, systemic treatment with MRK16 was more effective in inhibiting tumorigenicity and growth of MCP-1-gene-transfected cells than that of mocktransfected cells in a nude mouse model. We also show that the MCP-1-gene-transfected cells could produce regression of bystander tumor cells in the combination with MRK16. MATERIAL AND METHODS Cell linesThe human small-cell lung cancer H69 and its etoposide (VP-16) resistant variant H69/VP were kindly supplied by Dr. N. Saijo (Tokyo, Japan). His group previously showe...

Background: Recent our reports showed that 3-T pseudocontinuous arterial spin labeling (3-T pCASL) magnetic resonance perfusion imaging with dual post labeling delay (PLD) of 1.5 and 2.5 s clearly demonstrated the hemodynamics of ictal hyperperfusion associated with non-convulsive status epilepticus (NCSE). We aimed to examine the utility of 1.5-T pulsed arterial spin labeling (1.5-T PASL), which is more widely available for daily clinical use, for detecting ictal hyperperfusion. Methods: We retrospectively analyzed the findings of 1.5-T PASL with dual PLD of 1.5 s and 2.0 s in six patients and compared the findings with ictal electroencephalographic (EEG) findings. Results: In patients 1 and 2, we observed the repeated occurrence of ictal discharges (RID) on EEG. In patient 1, with PLDs of 1.5 s and 2.0 s, ictal ASL hyperperfusion was observed at the site that matched the RID localization. In patient 2, the RID amplitude was extremely low, with no ictal ASL hyperperfusion. In patient 3 with lateralized periodic discharges (LPD), we observed ictal ASL hyperperfusion at the site of maximal LPD amplitude, which was apparent at a PLD of 2.0 s but not 1.5 sec. Among three patients with rhythmic delta activity (RDA) of frequencies <2.5 Hz (Patients 4–6), we observed obvious and slight increases in ASL signals in patients 4 and 5 with NCSE, respectively. However, there was no apparent change in ASL signals in patient 6 with possible NCSE. Conclusion: The detection of ictal hyperperfusion on 1.5-T PASL might depend on the electrophysiological intensity of the epileptic ictus, which seemed to be more prominent on 1.5-T PASL than on 3-T pCASL. The 1.5-T PASL with dual PLDs showed the hemodynamics of ictal hyperperfusion in patients with RID and LPD. However, it may not be visualized in patients with extremely low amplitude RID or RDA (frequencies <2.5 Hz).